Fatty acids are a class of carboxylic acids with a long aliphatic tail. Many fatty acids are derived from triglycerides or phospholipids; they serve as critical sources of fuel in our body. There is accumulating evidence showing that chronically elevated plasma fatty acid leads to pathophysiological disorders. The elevated fatty acid levels in circulation are associated with the pathogenesis of diabetes, obesity and atherosclerosis (reviewed in 1-3). The intracellular trafficking of fatty acids requires a cluster of specific carrier proteins, named fatty acid-binding proteins (FABPs). Fatty acids directly bind to FABPs with high affinity, and the fatty acid-FABP complex are transported in cytoplasm for metabolic process or storage (4, 5).
The adipocyte FABP, FABP4 (aP2), is highly expressed in adipocytes. FABP4 plays an important role in various aspects of metabolic disorders, including insulin resistance, diabetes, and atherosclerosis. Insulin resistance can be observed in high-fat diet-fed mice; deficiency of FABP4 partially protects these mice against the development of insulin resistance. In addition, FABP4-deficient mice exhibits better performances in both insulin and glucose tolerance tests (6). Apart from genetic approaches, the blockade of FABP4 by small molecules could potentially mimic the phenotype of FABP4-deficient mice (6). Therefore, pharmacological agents that inhibit FABP4-mediated responses might serve as potential candidates for the treatment of insulin resistance, diabetes, and atherosclerosis (7).
FABP4 has recently been reported to interact directly with the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), triggering the ubiquitination and the subsequent proteasomal degradation of PPARγ (8). BMS309403, the well-characterized FABP4 inhibitor, up-regulated the basal protein levels of PPARγ (9). The elevation of PPARγ induced adipogenesis in adipose tissue, which is a significant adverse effect of PPARγ activation (10). The fatty acid binding pocket of FABP4 is distinct from the interaction site of FABP4 and PPARγ (8). In this respect, BMS309403 binding to FABP4 might lead to an allosteric regulation of FABP4, and therefore resulting in the elevation of PPARγ protein expression (8).
The expenditure of research and development (R&D) increased dramatically over past two decades. The pharmaceutical industries are keen to several strategies to reduce the cost of new drug development. The strategy of U.S. Food and Drug Administration (FDA)-approved drug repurposing aims to identify new uses for existing drugs. Given that the favorable pharmacokinetic and toxicological profiles of existing drugs in human subjects have been well characterized, a collection of FDA-approved drugs can be powerful resources for new indications discovery (11-16). For example, ciclopirox olamine is a synthetic antifungal drug for topical dermatologic treatment of superficial mycoses. Recently, ciclopirox olamine has been identified as a novel intracellular iron chelator, which exhibited anticancer activity in both in vitro and in vivo studies (17). The latest clinical trials reported that ciclopirox olamine displayed biological activity, which is now in Phase I study in patients with advanced hematologic malignancies (18).
In the present invention, a ligand library containing about 1500 compounds from FDA-approved drugs was compiled to search for ligand of human FABP4 for potential drugs of metabolic disorders. The present invention hereby describes the uses of small chemical molecules as FABP4 inhibitors and drugs for the treatment of metabolic diseases or cardiovascular diseases.